Chemistry and Metabolism of Biomolecules #10: Metabolism of Glucose (Part 3).

Introduction

The body can be considered an economist as it has devised a lot of proven and tested means of managing resources. The body orchestrates a lot of mechanisms and processes in an attempt to conserve life and also curtail wastage. An example is seen in the metabolism of glucose where lipids and other non-carbohydrate resources are converted to glucose in an attempt to provide the body with energy.

To set things straight, I will love to point out that glucose is the primary source of energy for the body. What this statement implies is, the body will always work towards obtaining energy from glucose and it will even go as far as converting other molecules that bear no exact “biochemical resemblance” with glucose to glucose all in an attempt to make glucose its primary source of energy.

Biochemical pathways are perfect representations of sequential reactions that lead to the production of an ultimate product(s). In a biochemical pathway, the product of a preceding reaction serves as a substrate (or as a chemist would say, reactant) for the next reaction. This is necessary in maintaining the sequence. Everything basically is interconnected.

The Gluconeogenic Pathway: Our Saving Grace in Periods When Our Glycogen Stores are Depleted.

The gluconeogenic pathway offers a means for glucose to be synthesised from non-carbohydrate sources. Humans and other mammals alike are known to store glucose as glycogen. The storage of glucose as glycogen occurs majorly in two places; The Muscles and The Liver. These are the main glycogen stores. The glial cells found in the brain also store glycogen but in very minute amounts.

These glycogen stores are just basically ways cells prepare for future shortages of glucose (their primary source of energy). These glycogen stores are under regulation by two primary hormones; Glucagon and Insulin.

Matter-of-factly speaking, the main way insulin and glucagon can alter the concentration of glucose in blood is by altering the amount of glycogen in these stores. Here is a breakdown of what happens. When you take a carbohydrate rich meal, there is a sudden rise in your blood glucose level since all carbohydrates are basically converted to glucose at the end of the day.

Insulin ensures the blood glucose level stays normal (Below 100 mg/dl – fasting, Below 200 mg/dl – random) during this sudden rise in blood glucose level by orchestrating the conversion of glucose to glycogen. It does this by increasing the expression of glucose transporters which are necessary in taking up blood glucose. These transporters are predominant on the cells of the muscles and liver. It is therefore of little or no wonder why these cells act as glycogen stores.

Glucagon acts in an opposite manner and under a different condition. Glucagon only comes into play during a drop in blood glucose level. It prevents the uptake of glucose by cells while ensuring the breakdown of glycogen into glucose to ensure its release into blood. This is done to increase the blood glucose level in an attempt to the meet the normal blood glucose value. So one can say that the hormones; insulin and glucagon are the main regulators of glycogenesis (synthesis of glycogen) and glycogenolysis (breakdown of glycogen).

In periods of extreme starvation and prolonged exercise, these glycogen stores are depleted. There is no supply of glucose since there is no consumption of carbohydrates. The cells know they need glucose badly. What do they do ? Other molecules must surrender their identities, become glucose and offer themselves as sacrifices to the cells. How is this (surrendering identities and becoming glucose) achieved ? By Gluconeogenesis of course.

Gluconeogenesis is the means by which non-carbohydrate three carbon compounds (lactate, pyruvate and glycerol) are converted to glucose. This pathway looks somewhat like the reversal of glycolysis but the three irreversible steps seen in glycolysis make the argument that gluconeogenesis is the direct reversal of glycolysis useless.

Only seven steps of gluconeogenesis are the direct reversals of glycolysis as they are catalyzed by the same enzymes seen in glycolysis. The three remaining steps proceed via special and different mechanisms and require enzymes different from the ones seen in glycolysis.

The gluconeogenic pathway keeps going by bypassing the three irreversible steps seen in glycolysis via special mechanisms and with different enzymes. These three steps are known as the bypass reactions of gluconeogenesis.
The gluconeogenic pathway begins with the conversion of pyruvate to phosphoenolpyruvate. This cannot just proceed as a reversal of the last step of glycolysis catalyzed by pyruvate kinase (phosphoenolpyruvate is converted to pyruvate). This step is split into two mini-steps.

Pyruvate is first converted to oxaloacetate with the hydrolysis of ATP catalyzed by the enzyme pyruvate carboxylase. A CO₂ molecule is basically attached to pyruvate giving rise to oxaloacetate. This is done to activate pyruvate for the next reaction.

The next mini-step within the pyruvate-phosphoenolpyruvate step is the conversion of oxaloacetate to phosphoenolpyruvate. Here, the CO₂ molecule which was attached earlier is lost with a corresponding attachment of a phosphoryl group. The donor of this phosphoryl group in this case is Guanosine Triphosphate (GTP) and not our usual Adenosine Triphosphate (ATP). What is the ultimate result of having to employ two reactions within a single step? Formation of phosphoenolpyruvate which is the ultimate goal of this step.

The second bypass reaction is seen where fructose 1, 6-bisphosphate is converted to fructose-6-phosphate. The enzyme here is Fructose 1,6-bisphosphatase and not phosphofructokinase which is seen in glycolysis. The mechanism is quite not the opposite as would be seen in a reversible reaction. The phosphoryl group at carbon 1 of fructose 1,6-bisphosphatase is lost in order for fructose 6-phosphate to be formed. The phosphoryl group is not lost to ADP as would be expected since the alternate reaction in glycolysis involves the hydrolysis of ATP to ADP.

One would expect the phosphoryl group to be transferred back to ADP as a reversal of the afore-mentioned step but this is simply not the case. The phosphoryl group is lost as P_i on hydrolysis of the carbon-1 phosphate. This makes this step biochemically different from the corresponding step seen in glycolysis as ATP is not formed.

The third bypass reaction is seen where glucose 6-phosphate is converted to glucose. This step is catalyzed by glucose 6-phosphatase and not hexokinase as would be expected in a reversible reaction. Also, ATP is not formed as would be expected but there is a loss of the phosphoryl group at carbon 6 of glucose as P_i.
These three steps make the gluconeogenic pathway irreversible and essentially different from the glycolytic pathway. The other seven steps are the direct reversals of the glycolytic pathway which I have talked about in one of the previous installments of this series.

Glycogenesis and Glycogenolysis: Two Processes the Body Uses to Keep The Blood Glucose Level at Normal.

Glycogen can be broken down to glucose in muscle and liver catalyzed the enzyme Glycogen phosphorylase. The glucose molecules have different metabolic fates in both muscles and the liver. The glycogen broken down in muscles is converted to glucose 6-phosphate ultimately which must go into the glycolytic pathway to provide energy which is needed for muscle contraction.

In the liver, it is a little different. The liver contains glucose 6-phosphatase which can convert glucose 6-phosphate to glucose in order to replenish the blood glucose in periods of low blood glucose levels. The muscles lack this enzyme so muscles do not really play a role replenishing glucose in blood. The glucose 6-phosphatase is found in the endoplasmic recticulum and so glucose 6-phosphate must be transported to the ER before it can be converted to glucose. This is another case of compartmentalization as this ensures that glucose 6-phosphatase does not interrupt glycolysis by actively converting glucose 6-phosphate to glucose. Glycolysis takes place in the cytosol while glucose 6-phosphatase acts in the endoplasmic recticulum.

Biochemically, glycogenolysis begins with the action of glycogen phosphorylase on glycogen. This enzyme targets the non-reducing ends of glycogen yielding glucose 1-phosphate. Phosphoglucomutase comes in to convert glucose 1-phosphate to glucose 6-phosphate which enters glycolysis in muscles or is converted to glucose in the liver. Glycogen phosphorylase cannot act at branching points and glycogen is heavily branched. This calls for the action of another enzyme; debranching enzyme which removes the branches ensuring that glycogen phosphorylase continues its action.

Glycogenesis begins with the conversion of glucose 6-phosphate to glucose 1-phosphate catalyzed by phosphoglucomutase. The nucleotide, Uridine Triphosphate (UTP) plays a vital role in glycogen syntheis. UTP combines with glucose 1-phosphate leading to the formation of UDP-glucose and a pyrophosphate (two phosphate molecules as one molecule) molecule. Attachment of a nucleotide to a monosaccharide is the way cells use to activate monosaccharides for biosynthetic reactions. Glycogen synthase then comes into play as it catalyses the addition of glucose (with the release of UDP) to an already exisiting glycogen chain.

The inevitable question is, if glycogen synthase is known to only add glucose to an already exisiting chain, how then is the already existing chain formed ? This is where glycogenin comes into play. Eight glucose molecules are assembled on glycogenin which catalyses the formation of the glycogen molecule that serves as a template for the addition of more glucose molecules by glycogen synthase. Glycogen is a branched molecule as I stated earlier so this means branches must be introduced in the newly formed glycogen molecule. This calls for the enzyme known as branching enzyme which is known to introduce in branches in glycogen.

Glycogenesis is activated during a rise in blood glucose level as a way to move glucose from the blood into cells while glycogenolysis is activated during a drop in blood glucose level as a way to move glucose from the cells to the blood.

Summary

Gluconeogenesis offers a way for non-carbohydrate molecules to be converted to glucose during desperate times. The roles of insulin and glucagon in glycogen metabolism have been pointed out. Glycogenesis and Glycogenolysis are the mechanisms behind the blood glucose altering actions of insulin and glucagon respectively.

References

^{Lehninger, A. L., Nelson, D. L., & Cox, M. M. (2000). Lehninger principles of biochemistry. New York: Worth Publishers. pp. 543-548 & 562-571.
Berg, J. M., TyMoczko, J. I & Stryer, L. (2002). Biochemistry (5th Edition). New York. W.H. Freeman. pp. 676-689.
Murray, R. K., Granner, D. K., Mayes, P. A. and Rodwell, V. W. (2012). Harper’s Illustrated Biochemistry. (30th Edition). Lange Medical Books. New York. pp. 185-194.}

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